Trypanosomes are parasites that cause a number of important diseases that are widespread in developing countries, including African sleeping sickness or trypanosomiasis. S-adenosyl-L-methionine decarboxylase (SAMDC) is a crucial enzyme in the biosynthesis of certain polyamines, such as spermidine and spermine. Inhibition of the production of these polyamines is detrimental to the survival and life cycle of certain microorganisms, including trypanosomes, thus inhibitors of SAMDC are useful to treat disorders such as trypanosomiasis.
Trypanosomiasis remains prevalent throughout sub-Saharan Africa, and includes both acute and chronic stages, and is caused by either of two trypanosomes, T. brucei gambiense and T. brucei rhodesiense. The chronic stage occurs where the trypanosome has invaded the CNS. It has been shown that inhibitors of polyamine biosynthesis, including ornithine decarboxylase inhibitors such as eflornithine (difluoromethyl ornithine), can inhibit growth of trypanosomes, and there is evidence that inhibitors of S-adenosylmethionine decarboxylase can also control trypanosome growth. C. J. Bacchi, et al., Antimicrobial Agents and Chemotherapy, 40 (6), 1448-53 (1996).
One known inhibitor of SAMDC is shown in FIG. 1: it is a mechanism-based inhibitor that irreversibly inhibits the enzyme. SAMDC decarboxylates SAM by the mechanism depicted in FIG. 2; inhibition of SAMDC by this compound is believed to operate by the mechanism depicted in FIG. 3. However, it has limited in vivo activity, which is believed to be due to rapid clearance and poor ability to cross the blood-brain barrier. The compound shows effective antitrypanosomal activity in cell based assays and in non-CNS trypanosome-infected mice models (FIG. 1). The compound, however, is not an ideal drug candidate because of its non-optimal pharmacokinetic profile and poor brain blood barrier penetration.
Other anti-trypanosome drugs are also known, including pentamidine, suramin, melarsoprol, eflornithine, and nifurtimox. However, all of these suffer from certain limitations, such as toxicity, complicated dosing regimens, susceptibility to resistance, lack of complete selectivity for enzymes in trypanosomes, poor pharmacokinetics, and poor transport across the blood-brain barrier to attack the CNS-active stage of trypanosomiasis. Therefore, there is a need for improved drugs to treat trypanosome infections, and for inhibitors of SAMDC that have increased bioavailability and ability to penetrate the blood-brain barrier. It has now been found that certain compounds of formula described herein inhibit SAMDC, and also inhibit trypanosome proliferation in vitro in a cell-based assay system. Without being bound by theory, it is believed that the inhibitors are mechanism-based inhibitors of SAMDC, and that their anti-trypanosomal activity is due to inhibition of SAMDC. These compounds exhibit improved pharmacokinetics, so their in vitro activity translates more efficiently into in vivo biological activity.